The A4 Trial studies anti-amyloid therapy for prevention of cognitive decline in cognitively healthy participants with brain amyloid on PET scans. This study adds wrist actigraphy to assess links of sleep and rest/activity rhythms with amyloid burden, and the effect of anti-amyloid therapy on sleep and rhythms.

Team: Paul Rosenberg, Adam Spira, Mark Wu, Vadim Zipunnikov
Funding: 1R01AG049872-01  (MPIs: Rosenberg & Spira)  07/15/2015 – 03/31/2020

Dementia and cognitive impairment are growing public health concerns. Knowledge of the importance of sleep-disordered breathing in the development of dementia, and particularly in the development of Alzheimer’s type of dementia (associated with β-amyloid deposition and neurodegeneration) is critical as it may lead to distinct avenues for development of therapies to prevent dementia or slow its progression. We propose to study the extent to which sleep-disordered breathing is associated with neuroimaging evidence of amyloid deposition, brain atrophy, and cognitive decline almost 20 years later.

Team: Adam Spira, Rebecca Gottesman, Mark Wu, Naresh Punjabi, Vadim Zipunnikov
Funding: 1RF1AG050745 (MPIs: Spira & Gottesman) 06/01/2016 – 05/31/2021

This project evaluates data from consumer wrist activity monitors in order to characterize sleep and circadian tendencies in the general population. Based on Under Armour wrist actigraphy monitoring, the project has developed novel tools and algorithms for classifying common sleep disorders in the general population. It is designed to provide tools and insights that help end-users improve their sleep and related outcomes including athletic performance, injury rates, cold susceptibility and general well-being. The project is currently being extended to a group of collegiate athletes in whom time constraints from practice schedules and academic and social demands can impact on sleep health.

Team: Alan Schwartz, Luu Pham, Frank Sgambati
Funding: Under Armour
Links: Hopkins and Under Armour Bring Science to Connected Fitness

This research will identify epigenetic modifications and changes in gene/protein expression associated with poor sleep and sleep-disordered breathing; the subset of those changes linked to AD biomarkers, measures of brain aging, and cognitive impairment; and links of poor sleep and SDB with accelerated cellular aging.

Team: Adam Spira, Mark Wu, Brion Maher, Susan Resnick, Luigi Ferrucci
Funding: Johns Hopkins University Catalyst Award

Upper airway obstruction (UAO) during sleep may be a source of cardiovascular stress in persons with Marfan syndrome. We are examining the effects of nocturnal UAO on hemodynamic function as well as on aortic and cardiac wall stress in persons with Marfan syndrome having haploinsufficient and dominant negative genotypes. This project will be the first to uncover UAO as a new mechanism for increased cardiovascular morbidity in Marfan syndrome and will also demonstrate the effect of CPAP treatment as a potential intervention for adverse cardiovascular events in Marfan syndrome.

Team: Mudiaga Sowho, Enid Neptune, Jonathan Jun, Susheel Patil, Gretchen MacCarrick, Hartmut Schneider.
Funding: NIH- 5 T32 HL 110952-5 (07/17- 06/20)​

Many populations reside at high altitude and are exposed to chronic low oxygen levels. During sleep, oxygenation plummets even further and triggers breathing pauses. We are studying the impact of altitude and low oxygen levels during sleep as part of the CRONICAS Cohort study, which has a high altitude site at Puno, Peru (3825 m, or 2.5 miles above sea level). We found that the prevalence of sleep apnea increased in proportion to reductions in oxygen levels during wakefulness and that patterns of oxygenation during sleep predicted worsening glucose control and chronic mountain sickness. Our current work focuses on developing inexpensive and readily deployable treatments for sleep apnea and low oxygen levels in highlanders.

Team: Luu Pham, Alan Schwartz, William Checkley, Dina Goodman
Funding: NIH  (Schwartz & Checkely) 1R34HL135360-01

Early exposure to iron deficiency during pregnancy and in infancy and childhood appears to increase risk of developing restless leg syndrome (RLS), a common debilitating disease, later in life. Epigenetic changes may provide an important link between prior iron deficiency and later disease development.  Epigenetic changes in CpG methylation in lymphocytes is the primary source of DNA. As iron deficiency anemia is associated with 6-fold increase in RLS expression, we utilize a population of women with iron deficiency anemia in which we delineate two groups: disease-susceptible and disease-resistant groups.

Team: Christopher Earley, Richard Allen, Satish Shanbhag, Rahki Naik, Peter van Zijl, Xi Li, Zachary Kaminsky. Coordinators : Alaina Hergenroeder and Emily Rost
Funding: NIH R01 NS101283 (Earley) 6/1/17-5/31/22

Sleep disturbances and sleep apnea have been implicated in pregnancy complications including gestational diabetes and preeclampsia. However, limited attention has been directed at understanding how maternal sleep disruption directly affects the fetus. We are examining immediate and persistent effects of maternal sleep disruption and maternal sleep-disordered breathing during pregnancy on the developing fetus.

Team: Janet DiPietro, Grace Pien, Janice Henderson, Frank Sgambati, Heather Watson
Funding: NIH R01HD079411 (DiPietro) 7/7/14-6/30/19

Sleep apnea patients are at increased risk for diabetes and cardiovascular disease, but mechanisms are unclear.  Our laboratory is studying effects of sleep apnea on nocturnal metabolism sleeping with or without wearing their CPAP.  Using this approach, we discovered that OSA increases plasma free fatty acids (FFA) and glucose during sleep.   Now, we are examining the underlying mechanisms and consequences of OSA-induced FFA elevation using techniques such as beta blockade and stable isotopes.

Team: Jonathan Jun, Chenjuan Gu, Robert Wolfe (UAMS), Elisabet Borsheim (UAMS), Alice Ryan (Univ of Maryland)
Funding: R01HL135483 (Jun) 2/1/2018 – 1/1/2023; R03HL138068 (Jun) 9/1/17 – 7/31/19
Links:

Enrollment: https://is.gd/miicstudy

https://clinicaltrials.gov/ct2/show/NCT02824263

https://clinicaltrials.gov/ct2/show/NCT03049306

https://www.hopkinsmedicine.org/johns_hopkins_bayview/research_clinical_trials/clinical_trials/sleep.html

The timing of meals may be important for weight control and heart health. Eating meals later in the day is linked with obesity and cardiovascular disease.  We hypothesize that eating close to bedtime may delay the oxidation of fat impair nocturnal metabolism.  To test this hypothesis we are performing a randomized trial of eating dinner before or after dim light melatonin onset (DLMO).

Team: Jonathan Jun, Chenjuan Gu, Daisy Duan, Luu Pham, Vsevolod Polotsky
Funding: Pilot
Links: https://dinnertimestudy.net/

Sleep apnea causes periods of low oxygenation. Although sleep apnea is strongly linked to metabolic diseases, the mechanisms for development of these metabolic diseases is unknown. Low oxygen levels during wakefulness increases blood glucose and markers of inflammation. The effects of low oxygen during sleep on metabolism have not been well studied. We are recruiting healthy volunteers in a study to examine the effects of breathing low oxygen on metabolism and gene expression in inflammatory pathways during sleep.

Team: Luu Pham and Alan Schwartz
Funding: The American Heart Association (Pham) 07/01/17-06/30/19, 17MCPRP3367111

Poor sleep may contribute to cognitive decline and progression of Alzheimer’s Disease. To study this phenomenon we will collect wrist actigraphy data for seven 24-hour periods in the Baltimore Longitudinal Study of Aging, which contains repeated measures of cognition with adjudication of cognitive status, [11C]-Pittsburgh compound B (PiB) positron emission tomography (PET)-measured β-amyloid, and structural magnetic resonance imaging (MRI)-measured atrophy. Participants who are cognitively normal at baseline and complete PiB PET will also complete polysomnography, permitting us to determine the extent to which poor sleep and altered rest/activity rhythms are prospectively associated with neuroimaging biomarkers of β-amyloid deposition and neurodegeneration, and with cognitive decline.

Team: Adam Spira, Mark Wu, Naresh Punjabi, Vadim Zipunnikov, Ciprian Crainiceanu, Susan Resnick, Eleanor Simonsick, Luigi Ferrucci
Funding: 1R01AG050507-01            (Spira)                         09/01/2015 – 05/31/2020

RLS is increased in prevalence and severity in patients that have iron deficiency anemia.  This study examines (1) whether intravenous iron therapy can more effectively improve symptoms and (2) whether treating the symptoms is more important than simply treating the anemia. This is a three-phase clinical trial. Phase I: randomized, double-blind, placebo-controlled 6-week assessment of treatment with 1500 mg ferric carboxymaltose. Phase II: open label, treatment with 1500 mg ferric carboxymaltose in non-responders in Phase I. Phase III: 46-week follow up with intermittent treatment with 750 mg ferric carboxymaltose if patients have a return of RLS symptoms and their ferritin < 300 ug/l.

Team: Christopher Earley (PI), Richard Allen, Satish Shanbhag, Rahki Naik, Peter van Zijl, Xi Li. Coordinators: Emily Rost and Alaina Hergenroeder.
Funding: Luitpold Pharmaceutical, Inc. Protocol VIT 15042. IND #73076
Links: NCT02826681

Sleep fragmentation is common in children admitted to the hospital during a time of neurocognitive development. Sleep disturbances that begin in the Pediatric ICU may have lasting impacts including psychological and psychiatric morbidities. Abnormal sleep-wake patterns may increase the risk of delirium and also decreases patient participation in early mobilization activities. We are investigating the impact of sleep fragmentation on delirium incidence and early mobilization. In addition, we are collaborating with Under Armour to develop an intervention utilizing fitness trackers for adolescents in the hospital.

Team: Sapna Kudchadkar, Tracie Walker, Aaron Hsu, Sean Barnes
Partners/funding: 1R21HD093369-01,  Under Armour

Obesity hypoventilation syndrome (OHS) leads to carbon dioxide elevation in a subset of obese patients.  There are few effective treatments for OHS.  In this clinical trial we are examining whether OHS can be improved by a short-term ketogenic diet.  Interested patients can apply using this survey link: https://redcap.link/ketohs

Team: Jonathan Jun, Chenjuan Gu, Luu Pham, Vsevolod Polotsky

Links: https://clinicaltrials.gov/ct2/show/NCT04108819

Enrollment: https://redcap.link/ketohs

Obesity or a high-fat diet can aggravate airway hyper-reactivity and asthma.  Furthermore, air pollution with particulate matter can induce or exacerbate asthma.  Our laboratory is investigating the interaction of particulate matter with diet on airway physiology and inflammation in mice.  We hope that this project will lead to an understanding of the relationship between asthma, nutrition, and air quality and provide possible targets for intervention.

Team: Seva Polotsky
Funding: P50 ES018176 (Hansel) 9/1/15-08/31/19
Links: https://www.polotskylab.net/

The pathogenesis of sleep apnea has been linked to a defect in neuromuscular control of the pharynx.  Our laboratory has pioneered a technique to augment upper airway patency by deploying designer receptors exclusively activated by designer drug (DREADD) in the hypoglossal motor neuron of mice.  Activation of the DREADDs dilated the pharynx.  We are now refining our technique by improving the specificity of DREADD delivery, using Cre-Lox technology and retrograde viral transfection techniques.

Team: Thomaz Fleury, Huy Pho, Seva Polotsky
Funding: R01HL138932 (Polotsky) 8/4/17 – 6/30/21; 16POST31000017 (Fluery) 7/1/16 -6/30/18
Links: https://www.polotskylab.net/

Airway narrowing and closure leading to sleep apnea occurs because of an excessive decrease in genioglossus muscle tone.   Thus, OSA may be treated by delivering electrical stimulation of the hypoglossal nerve, which controls the tone of the tongue muscle during sleep.  Already, one such device has been tested in clinical trials and is approved for OSA treatment in highly selected patients who cannot tolerate CPAP.   However, existing technology only stimulates the genioglossus muscle in a non-targeted manner which may limit its effectiveness.  Our laboratory is examining the effects of selective stimulation of various lingual muscles, singly or in combination, on upper airway function.

Team: Luu Phan, Vsevolod Polotsky, Thomaz Fleury
Funding:  lmThera, Inc.
Links: https://www.polotskylab.net/

Leptin is a hormone produced by adipose tissue that regulates appetite and metabolism.  Leptin deficient mice develop obesity.  It was later discovered that these mice also chronically hypoventilate, and replacing leptin improved ventilation and sensitivity to carbon dioxide.  Our lab also showed that replacing leptin improves upper airway function and sleep disordered breathing in mice.  Now, our lab is exploring signaling pathways of leptin in the brain to localize possible therapeutic targets.

Team: Huy Pho, Seva Polotsky
Funding: R01 HL128970 (Polotsky) 8/10/15 – 5/31/19
Links: https://www.polotskylab.net/

Leptin reduces food intake and increases metabolic rate.  However, leptin may be a “double-edged sword” since it can also increase blood pressure.  Our lab discovered that leptin binds to receptors on the carotid body and can increase blood pressure by activating channels in these cells.   Now, we are using viral transfection to manipulate leptin receptor expression in the carotid body, responses to leptin infusion.

Team: Mi-Kyung Shin, Seva Polotsky, James Sham
Funding: R01HL133100 (Polotsky) 7/1/16 – 2/29/20
Links: https://www.polotskylab.net/

Prolonged wakefulness (such as under conditions of sleep deprivation) is known to lead to increased rebound sleep. Our lab identified a novel neural circuit that encodes sleep drive in the fruit fly Drosophila melanogaster. We hypothesize that many signaling mechanisms resulting from behavioral states or environmental changes may act upon this circuit to suppress or increase sleep drive. Our team is currently working on identifying and characterizing the upstream signaling inputs and downstream targets of this homeostatic sleep circuit, as well as the molecular underpinnings of decision-making by this neural circuit. Findings arising from this research will shed light on the mechanisms of homeostatic regulation of sleep.

Team: Margaret Ho, Masashi Tabuchi, Ian Blum, Mark Wu
Funding: NIH R01NS100792-01A1 (Wu)
Links:  https://www.markwulab.net/